The main psychoactive component of marijuana is known as delta9-tetrahydrocannabinol (THC). In addition, it has recently been discovered that endogenous substances are synthesized in the brain that can activate cannabinoid receptors, and these substances are referred to as endocannabinoids. All drugs, both natural and synthetic, that act at receptors for this substance are known collectively as cannabinoids (CBs). Cannabinoid drugs obtained by the smoking or ingestion of marijuana are used illicitly presumably because they are reinforcing or rewarding to humans. One of the objectives of these studies is to gain knowledge about the underlying mechanisms through which cannabinoids alter brain cell function, and ultimately the mechanisms that produce the pleasurable effects of these drugs that sustain their illicit use. The primary focus of this laboratory is to examine the mechanisms through which abused drugs alter the electrical activity of neurons and the ways in which these neurons communicate with each other via synaptic connections. Therefore, one of our goals is to identify specific ion channels whose activity is modified by abused drugs such as marijuana, nicotine, heroin, and cocaine. To achieve these goals we utilize rat brain slices acutely obtained from discrete brain areas involved in processing information regarding pleasurable and unpleasant environmental stimuli. We utilize whole-cell electrophysiological recordings, and cellular anatomical techniques to reconstruct the neurons from which we record. In these ongoing studies we are examining the mechanisms through which these drugs affect neurons and their connections in the ventral tegmental area (VTA). This brain area and its connections are strongly implicated in the reinforcing and rewarding actions of all abused drugs, as well as in mediating the rewarding effects of natural environmental stimuli, such as food, water, etc. The VTA is also involved in processing information regarding the physiological stress responses, mood and affect, and mental alertness. Because of its central role in these processes, the VTA is a brain area that contributes to disorders such as addiction, psychiatric stress disorders, clinical depression, and psychiatric anxiety disorders. Recent studies in the laboratory have focused on delineating the relative contribution of synaptic inputs to the VTA dopamine neurons arising from distinct brain regions. One of the sub-cortical inputs to the VTA that we are currently studying is that from the pedunculopontine nucleus (PPN). This brain nucleus provides strong acetylcholinergic (Ach) input to the VTA, and therefore is likely involved in regulating the reinforcing and addictive properties of the drug nicotine. Therefore, these studies will provide information that will be useful in the treatment of nicotine addiction, as well as in the prevention of respiratory disorders, such as emphysema, and lung cancer, resulting from nicotine addiction. Moreover, since the PPN is known to be critical to setting states of alertness, and physiological arousal, it is strongly implicated as a subcortical brain structure involved in anxiety, and chronic stress disorders. Our most recent studies examine the properties of the PPN input to the VTA, with regard to nicotine sensitivity, as well as the ability of this pathway to undergo a long-term change know as long-term depression (LTD) following exposure to either environmental stress, cocaine or delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana. We have found that the PPN inputs to the VTA are inherently weaker than glutamate inputs arising from the cortex. Furthermore, we have found that these PPN inputs can be be strengthened if animals are exposed to stress, cocaine, or THC, and that nicotine exposure can alter the ability of the PPN to activate the reward-relevant dopamine neurons in the VTA. These data demonstrate that the strength of glutamatergic synaptic transmission on VTA dopamine neurons varies according to its source, and can be altered by commonly abused drugs. Additional studies are now being conducted to determine the site at which endogenous cannabinoid molecules are synthesized in brain reward circuits and where these molecules act to alter brain reward function. One hypothesis that is currently being explored is that there is a cooperation among synaptic inputs to VTA to summate and permit endocannabinoid production in VTA dopamine neurons. To test this we are activating subcortical inputs from the PPN that contain acetylcholine, just prior to the activation of glutamate inputs arising from several cortical inputs. Preliminary data suggest that the activation of multiple inputs to the same dopamine neurons is greater than additive in generating endogenous cannabinoid release from these cells. If this observation is substantiated then it suggests that some synaptic neural pathways can act as switches to control the activation of the endogenous cannabinoid system. As many studies have shown that endogenous cannabinoids play a significant role in altering the addictive potency of many abused drugs, our studies may point to critical mechanisms that can weaken the effects of these drugs on this critical component of the brain's reward pathway.